Many of the cells of the immune system express receptors for neuroactive molecules which modulate immune system function, creating a link between the nervous and immune systems (Nio et al. (1993) J Immunol. 150:5281-5288; Torcia et al. (1996) Cell 85:345-356).
xcex3-Aminobutyric acid (GABA) is a ubiquitous inhibitory neurotransmitter in the central nervous system (CNS; reviewed in Erdo and Wolff (1990) J. Neurochem. 54:363-372; Olsen and Tobin (1990) Faseb J. 4:1469-1480; Kaufmnan and Tobin (1993) Trends Pahrmacol. Sci. 14:107-109; Macdonald and Olsen (1994) Ann. Rev. Neurosc. 17:569-602; and Luddens et al. (1995) Neuropharmacology 34:245-254). GABA is synthesized from glutamic acid by the enzyme glutamate decarboxylase (GAD; reviewed in Erlander et al. (1991) Neuron 7:91-100). Outside of the brain, GAD and GABA receptors have been reported in the pancreatic islets, the gastrointestinal tract, ovaries and adrenal medulla (Erdo and Wolff (1990), supra).
There are at least two types of neuronal GABA receptors, GABAA and GABAB. GABAA receptors are ligand-gated ion channels which respond to GABA by opening their integral C1xe2x88x92 channel (Olsen and Tobin (1990); Macdonald and Olsen (1994); Luddens et al. (1995); all supra). Pharmacologically, muscimol acts as an agonist for GABAA receptors and anxiolytic benzodiazepines as well as anesthetic agents (such as pentobarbital) potentiate the opening of the GABAA-C1xe2x88x92 channel. Bicuculline and RU5315 antagonize GABAA receptor function and picrotoxin blocks the GABAA receptor C1xe2x88x92 channel (Macdonald and Olsen (1994); and Luddens et al. (1995); both supra). In contrast, GABAB receptors are coupled to Ca2+ or K+ channels via GTP-binding proteins and are selectively activated by baclofen (Bowery (1993) Annu. Rev. Pharmacol. Toxicol. 33:109-147). GABAB receptors are insensitive to bicuculline and picrotoxin. The administration of GABA or its agonists peripherally inhibits antibody production and modulates macrophage phagocytosis in vivo (Ratnikov et al. (1982) Biull. Eksp. Biol. Med. 94:56-58; and Frangulyan et al. (1986) xe2x80x9cInfluence of neuroactive amino acids on some indexes of natural immunityxe2x80x9d In: Neurohumoral regulation of Immune Homeostasis, Leningrad, Russia).
Many diseases, including allergies and autoimmune diseases, as well as graft rejection, result from a deleterious immune response. For example, more than 30 autoimmune diseases are presently known; these include many which have received much public attention, including myasthenia gravis (MG) and multiple sclerosis (MS). Characteristic of these diseases is the attack by the immune system on the tissues of the victimxe2x80x94these tissue antigens being non-immunogenic in non-diseased individuals because of their tolerance of the immune system to xe2x80x9cself.xe2x80x9d In autoimmune diseases, this tolerance apparently is compromised, and the tissue of the afflicted subject is treated as an invaderxe2x80x94i.e., the immune system sets about destroying this presumed foreign target. Furthermore, graft rejection results from the activation of T lymphocytes and allergic reaction are also due to an exacerbated immune response.
Alternatively, enhancing immune responses is useful for treating a number of diseases and infections. In addition, redirecting the immune response can result in a more efficient immunity against certain diseases. For example, a viral infection will be more efficiently eliminated if the immune response can be redirected from a predominantly antibody response to a protective Th1 cell-mediated response.
There is, therefore, a need in the art for methods to modulate the immune system to treat a variety of diseases. The present invention addresses these and other needs.
The present invention provides methods of modulating an immune response in a patient. The methods comprise administering an immunomodulatory amount of a compound that binds the GABA binding site within a GABAA receptor. The compounds are preferably administered orally, transdermally, intravenously, subcutaneously, or using a pump. The compound used in the method can be either an agonist or an antagonist of GABA. In one embodiment, the methods of the invention are used to down-regulate an immune response and the compound is a GABA agonist. These methods are particularly useful in treating diseases which involve a deleterious immune response such as autoimmune disease, allergy, and graft rejection. The methods may further comprise administering a GABA potentiator. In one embodiment, the potentiator binds to the benzodiazepine binding site within a GABAA receptor. In another embodiment, the potentiator binds to the barbiturate binding site within a GABAA receptor. In yet another embodiment the potentiator binds to the steroid binding site within a GABAA receptor.
The invention also provides methods in which the compound that binds the GABAA receptor is a GABA antagonist. These methods are used to enhance an immune response. The methods are particularly useful in enhancing a Th1-mediated immune response. Such methods are useful, for example, in enhancing immune response against certain pathogens such as viruses.